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Quick Reference
  • Normal Range: 0.8-1.8 ng/dL (assay-dependent; 10-23 pmol/L in SI units)
  • Alternative Name: FT4, Free Thyroxine
  • Fraction of Total T4: Only 0.03% of T4 is free; 99.97% bound to proteins
  • Primary Use: Confirm thyroid dysfunction after abnormal TSH; distinguish subclinical from overt disease
  • Sample Type: Serum
  • Key Point: Free T4 is metabolically active and not affected by binding protein changes (unlike Total T4)

Test Description

What is Free T4?

Free T4 (Free Thyroxine) measures the unbound, metabolically active form of thyroxine in the blood. While most T4 is bound to carrier proteins (thyroid-binding globulin, transthyretin, and albumin), only the free fraction can enter cells and exert physiologic effects.

Free vs. Bound T4

Understanding the distinction between free and bound T4 is essential:

  • Total T4: 99.97% bound to proteins (mainly TBG), 0.03% free
  • Free T4: Only the 0.03% unbound fraction - this is what enters cells and regulates metabolism
  • Protein binding: TBG binds ~75%, transthyretin ~15%, albumin ~10% of circulating T4
  • Dynamic equilibrium: Bound and free T4 exist in equilibrium; as free T4 is consumed, bound T4 is released
Why Free T4 is Better Than Total T4: Free T4 accurately reflects thyroid function regardless of binding protein levels. Total T4 can be misleading - pregnancy and estrogen increase TBG, raising Total T4 without hyperthyroidism. Nephrotic syndrome and cirrhosis decrease TBG, lowering Total T4 without hypothyroidism. Free T4 remains normal in these situations.

T4 as Prohormone for T3

T4 functions primarily as a reservoir and prohormone for the more potent T3:

  • Peripheral conversion: 80% of circulating T3 comes from T4 deiodination in peripheral tissues (liver, kidney, muscle)
  • Type 1 deiodinase (D1): Converts T4 to T3 in liver and kidney
  • Type 2 deiodinase (D2): Converts T4 to T3 locally in brain, pituitary, brown fat
  • Reverse T3: Alternative pathway produces inactive rT3 (increased in illness, fasting)
  • Potency difference: T3 is 3-4 times more metabolically active than T4

Levothyroxine is Synthetic T4

Levothyroxine (Synthroid, Levoxyl) is synthetic T4 and the standard treatment for hypothyroidism:

  • Conversion to T3: Body converts levothyroxine to active T3 via peripheral deiodinases
  • Long half-life: T4 half-life ~7 days allows once-daily dosing and steady plasma levels
  • Dose monitoring: Monitor TSH (not Free T4) for dose adjustment; TSH more sensitive
  • Steady state: Takes 6-8 weeks after dose change for TSH to equilibrate

Clinical Use

Free T4 is ordered alongside TSH for complete thyroid assessment:

  • After abnormal TSH: Confirms thyroid dysfunction and distinguishes subclinical from overt disease
  • Monitoring treatment: Tracks response to levothyroxine or antithyroid drugs (TSH is primary target)
  • Central hypothyroidism: Low Free T4 with inappropriately low/normal TSH suggests pituitary failure
  • Non-thyroidal illness: Helps distinguish sick euthyroid syndrome from true hypothyroidism
Normal Ranges

Free T4 reference ranges vary significantly between assays and laboratories. Always use lab-specific reference ranges. Values below represent typical ranges.

Swipe to see more
Population Free T4 (ng/dL) SI Units (pmol/L)
Adults 0.8-1.8 10-23
Pregnancy - 1st trimester 0.7-1.5 9-19
Pregnancy - 2nd/3rd trimester 0.6-1.4 8-18
Elderly 0.8-1.8 10-23
Children 0.8-2.0 10-26
Important Considerations:
  • Assay dependence: Free T4 assays vary widely; reference ranges can differ by 30-40% between methods
  • Direct vs. analog methods: Most labs use immunoassay (analog) methods; equilibrium dialysis is gold standard but rarely used
  • Pregnancy changes: Free T4 typically decreases slightly in pregnancy; use trimester-specific ranges
  • Conversion factor: ng/dL × 12.87 = pmol/L
  • Interference: Heparin, severe illness, and certain medications can affect Free T4 measurement
Clinical Significance

Elevated Free T4 (Hyperthyroidism/Thyrotoxicosis)

High Free T4 with suppressed TSH indicates primary hyperthyroidism:

Common Causes

  • Graves' disease: Most common; autoimmune with TSH receptor antibodies (TRAb/TSI positive)
  • Toxic multinodular goiter: Autonomous thyroid nodules producing excess hormone
  • Toxic adenoma: Single hyperfunctioning nodule
  • Thyroiditis (early phase): Subacute, postpartum, or silent thyroiditis causing transient thyrotoxicosis
  • Excessive levothyroxine: Over-replacement or intentional/factitious hyperthyroidism
  • Iodine-induced (Jod-Basedow): Hyperthyroidism from iodine exposure (contrast, amiodarone)
  • Struma ovarii: Rare ectopic thyroid tissue in ovarian teratoma
  • TSH-secreting pituitary adenoma: Very rare; high TSH + high Free T4 (not suppressed)

Low Free T4 (Hypothyroidism)

Low Free T4 with elevated TSH indicates primary hypothyroidism:

Primary Hypothyroidism

  • Hashimoto's thyroiditis: Most common; chronic autoimmune destruction (anti-TPO antibodies positive)
  • Post-radioactive iodine: Intentional ablation for Graves' disease or thyroid cancer
  • Post-thyroidectomy: Surgical removal of thyroid gland
  • Medications: Lithium, amiodarone (type 2), interferon-alpha, tyrosine kinase inhibitors
  • Iodine deficiency: Common worldwide; rare in iodine-supplemented regions
  • Congenital hypothyroidism: Thyroid dysgenesis or dyshormonogenesis

Central (Secondary/Tertiary) Hypothyroidism

Low Free T4 with low or inappropriately normal TSH suggests pituitary/hypothalamic failure:

  • Pituitary adenoma: Mass effect on thyrotrophs
  • Pituitary surgery/radiation: Iatrogenic hypopituitarism
  • Sheehan syndrome: Postpartum pituitary necrosis
  • Infiltrative disease: Sarcoidosis, hemochromatosis, lymphocytic hypophysitis
  • TRH deficiency: Hypothalamic injury from tumor or trauma
  • Key diagnostic clue: TSH should be HIGH in primary hypothyroidism; if TSH is low/normal with low Free T4, think pituitary

Normal Free T4 with Abnormal TSH

Subclinical Hypothyroidism (High TSH, Normal Free T4)

  • Definition: TSH >4.5 mIU/L, Free T4 normal; often asymptomatic
  • Progression: 2-5% annually develop overt hypothyroidism
  • Treatment threshold: Treat if TSH >10, symptomatic, positive TPO antibodies, or pregnant

Subclinical Hyperthyroidism (Low TSH, Normal Free T4)

  • Definition: TSH <0.4 mIU/L, Free T4 normal
  • Check Free T3: May have T3 toxicosis (normal Free T4, high Free T3)
  • Risks: Atrial fibrillation, osteoporosis if TSH <0.1 mIU/L
Interpretation Guidelines

TSH + Free T4 Interpretation Patterns

Always interpret Free T4 alongside TSH for accurate diagnosis:

Swipe to see more
TSH Free T4 Free T3 Interpretation
High Low Low/Normal Overt Primary Hypothyroidism
High Normal Normal Subclinical Hypothyroidism
Low High High/Normal Overt Primary Hyperthyroidism
Low Normal Normal or High Subclinical Hyperthyroidism or T3 Toxicosis
Low/Normal Low Low Central Hypothyroidism or Sick Euthyroid Syndrome
Normal Normal Normal Euthyroid (Normal)
When to Order Free T3: TSH and Free T4 are usually sufficient. Add Free T3 when:
  • Subclinical hyperthyroidism (low TSH, normal Free T4) - check for T3 toxicosis
  • Monitoring Graves' disease treatment - T3 may remain elevated when T4 normalizes
  • Suspecting thyrotoxicosis with confusing results
Free T3 is NOT useful for hypothyroidism diagnosis or monitoring.

Levothyroxine Monitoring

Free T4 plays a secondary role to TSH in levothyroxine dose adjustment:

Monitoring Strategy:
  • Primary target: TSH (0.5-2.5 mIU/L for most patients)
  • Free T4 role: Confirms adequate T4 replacement; typically mid-to-upper normal range on levothyroxine
  • Timing: Check TSH + Free T4 6-8 weeks after dose change
  • Discordant results: If TSH normal but Free T4 high, patient may be non-compliant and took dose just before testing
  • Over-replacement: Free T4 above normal range with suppressed TSH increases AF and osteoporosis risk

Non-Thyroidal Illness (Sick Euthyroid Syndrome)

Critical illness affects Free T4 without true thyroid disease:

Pattern in Critical Illness:
  • Typical pattern: Low T3, low/normal T4, low/normal TSH
  • Free T4 changes: Usually normal; may be low in severe illness
  • Mechanism: Decreased peripheral T4-to-T3 conversion; adaptive energy-conserving response
  • Management: DO NOT treat with thyroid hormone; increases mortality
  • Follow-up: Recheck 6-8 weeks after illness resolves; TSH may transiently rise during recovery
Interfering Factors

Medications Affecting Free T4 Levels

Medications That Increase Free T4:

  • Levothyroxine over-replacement: Excessive dose or recent dose ingestion
  • Heparin: In vitro artifact; releases fatty acids that displace T4 from binding proteins during assay
  • Amiodarone: Blocks T4-to-T3 conversion; increases Free T4 while decreasing T3

Medications That Decrease Free T4:

  • Antithyroid drugs: Methimazole, propylthiouracil (PTU) block T4 synthesis
  • Lithium: Inhibits thyroid hormone release
  • Amiodarone (type 2): Can cause destructive thyroiditis with hypothyroidism
  • Tyrosine kinase inhibitors: Sunitinib, sorafenib cause hypothyroidism
  • Immune checkpoint inhibitors: Nivolumab, pembrolizumab can cause thyroiditis

Medications Affecting Levothyroxine Absorption

These reduce levothyroxine absorption, potentially lowering Free T4 despite adequate dose:

  • Proton pump inhibitors (PPIs): Reduce T4 absorption by 20-30%; take levothyroxine on empty stomach
  • Calcium supplements: Binds T4 in GI tract; separate by 4 hours
  • Iron supplements: Forms complexes with T4; separate by 4 hours
  • Bile acid sequestrants: Cholestyramine, colestipol bind T4; separate by 4-6 hours
  • Soy products: May decrease T4 absorption if taken with levothyroxine
  • Fiber supplements: Reduce absorption if taken concurrently

Medications Increasing Levothyroxine Requirements

These increase T4 metabolism or clearance, requiring dose adjustment:

  • Estrogen/oral contraceptives: Increase TBG, raising bound T4; may need 25-30% dose increase
  • Anticonvulsants: Phenytoin, carbamazepine, phenobarbital induce hepatic metabolism
  • Rifampin: Potent inducer of T4 metabolism
  • Sertraline: May increase T4 requirements in some patients

Assay Interference

Factors causing falsely abnormal Free T4 results:

  • Biotin (high dose): >5 mg/day interferes with immunoassays; falsely high Free T4, falsely low TSH (mimics hyperthyroidism). Stop 48-72 hours before testing
  • Heterophile antibodies: Human anti-animal antibodies interfere with immunoassays
  • Severe non-thyroidal illness: Assay methods may give discrepant results in critical illness
  • Heparin therapy: In vitro artifact; causes falsely elevated Free T4 in some assays
  • Familial dysalbuminemic hyperthyroxinemia (FDH): Genetic variant with high albumin affinity for T4; normal TSH, high Total T4, normal Free T4 (by equilibrium dialysis)

Physiological Factors

  • Pregnancy: Free T4 may decrease slightly; use trimester-specific ranges
  • Age: Free T4 reference range relatively stable across age groups
  • Time of day: Less diurnal variation than TSH; Free T4 relatively stable
Clinical Pearls
Clinical Pearl
"Free T4 is more accurate than Total T4": Free T4 reflects metabolically active hormone and is not affected by binding protein changes. Total T4 is misleading in pregnancy (high TBG), liver disease (low TBG), or nephrotic syndrome (low TBG). Always order Free T4, not Total T4.
Clinical Pearl
"TSH first, Free T4 second": TSH is the best screening test. Order Free T4 to confirm abnormal TSH and distinguish subclinical from overt disease. Don't routinely order both together unless monitoring treatment or symptoms strongly suggest thyroid dysfunction.
"Normal Free T4 + abnormal TSH = subclinical disease": High TSH + normal Free T4 = subclinical hypothyroidism. Low TSH + normal Free T4 = subclinical hyperthyroidism (check Free T3 for T3 toxicosis). This pattern represents early or mild thyroid dysfunction.
"Low TSH + Low Free T4 = think pituitary, not thyroid": Primary hypothyroidism causes HIGH TSH as negative feedback loop tries to stimulate failing thyroid. If both TSH and Free T4 are low, suspect central (secondary) hypothyroidism from pituitary failure. Check other pituitary hormones and obtain MRI.
Clinical Pearl
Levothyroxine dose is guided by TSH, not Free T4: TSH is far more sensitive for detecting under- or over-replacement. Free T4 should be mid-to-upper normal range on adequate levothyroxine dose, but TSH (target 0.5-2.5 mIU/L) is the primary dosing guide.
Clinical Pearl
"T4 is a prohormone for T3": T4 is converted to T3 (3-4× more potent) in peripheral tissues. This is why levothyroxine (synthetic T4) is preferred over liothyronine (T3) - stable conversion provides steady T3 levels. Only 20% of T3 comes from thyroid; 80% from T4 conversion.
Biotin interference is common: Many supplements contain 5-10 mg biotin (far exceeding RDA). High-dose biotin causes falsely high Free T4 and falsely low TSH in immunoassays, mimicking hyperthyroidism. Always ask about supplements; stop biotin 48-72 hours before testing.
Take levothyroxine alone on empty stomach: Food, PPIs, calcium, iron, and fiber reduce T4 absorption by 20-50%. Take levothyroxine 30-60 minutes before breakfast or at bedtime (4 hours after dinner). Separate supplements by 4 hours. Consistency is key.
Clinical Pearl
Free T4 on upper end of normal is expected with levothyroxine: Well-treated hypothyroid patients typically have Free T4 in upper half of normal range with TSH 0.5-2.5 mIU/L. This is appropriate - don't reduce dose if Free T4 is high-normal with normal TSH.
Clinical Pearl
"Check for T3 toxicosis in subclinical hyperthyroidism": If TSH is suppressed but Free T4 is normal, order Free T3. Some patients have T3 toxicosis (high Free T3, normal Free T4) from early Graves' disease or toxic nodule preferentially secreting T3.
Pregnancy requires higher levothyroxine doses: T4 requirements increase 30-50% in pregnancy due to increased TBG, placental transfer, and fetal demand. Check TSH + Free T4 every 4-6 weeks during pregnancy. Target TSH <2.5 mIU/L in first trimester for fetal neurodevelopment.
Clinical Pearl
Amiodarone causes complex thyroid changes: Blocks T4-to-T3 conversion, causing high Free T4, low T3, and normal/slightly elevated TSH in euthyroid patients. Can also cause hypo- or hyperthyroidism. Check baseline TSH/Free T4 before starting and monitor every 3-6 months.
References
  1. Kratz, A., Ferraro, M., Sluss, P. M., & Lewandrowski, K. B. (2004). Laboratory reference values. New England Journal of Medicine, 351, 1548-1564.
  2. Lee, M. (Ed.). (2009). Basic skills in interpreting laboratory data. Ashp.
  3. Farinde, A. (2021). Lab values, normal adult: Laboratory reference ranges in healthy adults. Medscape. https://emedicine.medscape.com/article/2172316-overview?form=fpf
  4. Nickson, C. (n.d.). Critical Care Compendium. Life in the Fast Lane • LITFL. https://litfl.com/ccc-critical-care-compendium/
  5. Farkas, Josh MD. (2015). Table of Contents - EMCrit Project. EMCrit Project. https://emcrit.org/ibcc/toc/
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